Senolytic Therapy for Frailty

Overseen By Gregory T. Armstrong, MD, MSCE

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: CYP3A4 drugs, Anticoagulants

Disqualifiers: HIV, Hepatitis B/C, Anemia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 8

Duration: 32 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments, Dasatinib plus Quercetin (a senolytic therapy) and Fisetin, to determine if they can improve walking speed and reduce frailty in adults who survived childhood cancer. Researchers are also examining whether these treatments can decrease the number of senescent cells, which have stopped dividing and can impact health. The trial seeks to determine the safety and tolerability of these treatments. Ideal participants are cancer survivors for over five years who experience frailty, such as difficulty with walking speed and muscle strength. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications for the trial?

The trial requires you to stop taking certain medications, especially those that affect specific enzymes (CYP3A4, CYP2C8, CYP2C9, or CYP2D6) or if you are on anticoagulants or antimicrobial agents. If you are on anticoagulants or antiplatelet agents, you may need to pause them during the 2-3 day drug dosing period, but you can resume them afterward.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that both Dasatinib plus Quercetin and Fisetin have been studied for safety in different settings. Studies have found that Dasatinib plus Quercetin reduces signs of aging in mice, and human trials have reported no major safety issues. However, limited information on side effects in humans remains, so ongoing studies aim to gather more details.

For Fisetin, research has not identified any major safety problems in humans. Studies suggest it may help with aging-related issues by targeting cells that stop dividing and contribute to aging. No serious side effects have been reported with Fisetin supplements.

Researchers are exploring these treatments for their potential benefits in managing frailty in childhood cancer survivors. While early results seem promising, more data from ongoing research will help determine their safety and effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they target senescent cells, which are cells that have stopped dividing and can contribute to aging and frailty. Unlike standard treatments for frailty that often focus on physical therapy or nutritional support, Dasatinib plus Quercetin and Fisetin work at the cellular level to clear these "zombie" cells. This approach is unique because it addresses a root cause of frailty rather than just managing symptoms. Both treatments have the potential to not only improve physical strength and resilience but also reduce inflammation, offering a comprehensive boost to overall health.

What evidence suggests that this trial's treatments could be effective for frailty?

This trial will compare two treatments: Dasatinib plus Quercetin and Fisetin. Research has shown that combining Dasatinib and Quercetin may reduce frailty and improve movement and cognitive skills. Studies have found that this combination can lower inflammation and enhance overall health in older adults. It also helps remove old cells that no longer divide and can cause harm.

Fisetin, another treatment option in this trial, is known for its strong ability to combat damage in the body. It targets and reduces these old cells, potentially improving health and extending life. Early findings suggest that Fisetin can help manage long-term health issues by reducing cell damage. Both treatments aim to improve walking speed and reduce signs of aging in cells, offering hope for reducing frailty in childhood cancer survivors. ^{2 3 6 7 8}

Who Is on the Research Team?

Gregory T. Armstrong, MD, MSCE

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

Adults who survived childhood cancer and are now frail (meeting at least 3 of 5 specific health criteria), over 18 years old, more than 5 years post-diagnosis, with certain blood markers. They must be able to take oral meds, not pregnant or nursing, agree to use contraception due to teratogenic risks of Dasatinib, have no severe heart issues or anemia, and not on conflicting medications.

Inclusion Criteria

QTc <450 milliseconds in electrocardiogram

I am part of SJLIFE and was diagnosed over 5 years ago.

My test shows low levels of a specific protein in my immune cells.

Exclusion Criteria

I am currently taking blood thinners or antibiotics.

Pregnant or nursing at time of enrollment/during the study

I am not currently receiving treatment for any cancer except non-melanoma skin cancers.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Dasatinib plus Quercetin or Fisetin to reduce senescence and improve frailty

32 days

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

150 days

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Dasatinib plus Quercetin
• Fisetin

Trial Overview The trial is testing two treatments aimed at reducing cell aging and improving physical function in adult survivors of childhood cancer. One group will receive a combination of drugs called Dasatinib plus Quercetin; the other will get Fisetin alone. The main goals are better walking speed and fewer senescent cells in the blood.

How Is the Trial Designed?

Group I: Dasatinib plus Quercetin Active Control 1 Intervention

Day 0 (30 per arm, randomization stratified by sex and age) At the visit on day 7, blood CD3+ T lymphocyte p16\^INK4A mRNA and other markers of inflammation and senescence will be accessed to verify that senescent cells have been cleared by the intervention. Post-treatment follow-up will occur on days 60 for (primary endpoints) and day 150 for secondary evaluation. Day 150 will assess the permanence of change after completion of the trial.

Group II: Fisetin Active Control 1 Intervention

Day 0 (30 per arm, randomization stratified by sex and age) At the visit on day 7, blood CD3+ T lymphocyte p16INK4A mRNA and other markers of inflammation and senescence will be accessed to verify that senescent cells have been cleared by the intervention. Post-treatment follow-up will occur on days 60 for (primary endpoints) and day 150 for secondary evaluation. Day 150 to will assess the permanence of change after completion of the trial.

Dasatinib plus Quercetin is already approved in European Union, United States for the following indications:

Approved in European Union as Sprycel for:

• Chronic Myelogenous Leukemia
• Acute Lymphoblastic Leukemia

Approved in United States as Sprycel for:

• Chronic Myelogenous Leukemia
• Acute Lymphoblastic Leukemia

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The study identified six new potential senolytic compounds, including natural products like baicalein and luteolin, which may help reduce senescent cells and inflammation associated with aging.

This research utilized advanced computational methods to analyze over 40,000 molecules, marking the first proposal of these specific compounds as having senolytic activity, although further experimental validation is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natural Products as a Major Source of Candidates for Potential Senolytic Compounds obtained by in silico Screening. Barrera-Vázquez, OS., Magos-Guerrero, GA., Escobar-Ramírez, JL., et al.[2023]

Fisetin was identified as the most potent senolytic flavonoid among 10 tested, effectively reducing senescence markers in both murine and human tissues, indicating its potential for treating age-related conditions.

Treatment with fisetin in aged mice not only improved tissue health and reduced age-related pathology but also extended their median and maximum lifespan, suggesting promising implications for human clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fisetin is a senotherapeutic that extends health and lifespan. Yousefzadeh, MJ., Zhu, Y., McGowan, SJ., et al.[2021]

Senolytic drugs, particularly fisetin, have shown promise in reducing age-related bone density loss in a progeria mouse model, suggesting they may help combat osteoporosis in aging individuals.

The study highlights the potential of targeting senescent cells, which accumulate with age and contribute to various age-related conditions, as a strategy to improve bone health and overall quality of life in the elderly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24 -/- Progeria Mouse Model. Hambright, WS., Mu, X., Gao, X., et al.[2023]

Dasatinib, a multiple kinase inhibitor, is rapidly absorbed in the body after oral administration, with a peak concentration reached in about 30 minutes and a short elimination half-life of less than 4 hours, indicating efficient absorption and metabolism.

Most of dasatinib is eliminated through feces (85%), and while several metabolites are formed, they are not expected to significantly contribute to the drug's therapeutic effects, as the active metabolites do not show strong inhibitory activity against key kinases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolism and disposition of dasatinib after oral administration to humans. Christopher, LJ., Cui, D., Wu, C., et al.[2015]

In a 12-week pilot study involving 5 participants with early-stage Alzheimer's disease, the combination of dasatinib and quercetin was well-tolerated, showing safety and feasibility without significant adverse effects or early discontinuations.

The treatment successfully penetrated the central nervous system, with dasatinib detected in cerebrospinal fluid, suggesting potential for targeting cellular senescence in Alzheimer's, although cognitive improvements were not observed in this small trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Senolytic therapy to modulate the progression of Alzheimer's Disease (SToMP-AD) - Outcomes from the first clinical trial of senolytic therapy for Alzheimer's disease. Gonzales, MM., Garbarino, VR., Kautz, T., et al.[2023]

Dasatinib and quercetin (D&Q) effectively reduce markers of cellular senescence and inflammation in aging adipose tissue, which may help alleviate chronic inflammation associated with age-related diseases.

D&Q treatment improved metabolic functions in old mice, including better fasting blood glucose levels and glucose tolerance, suggesting potential for therapeutic use in combating metabolic dysfunction in aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age. Islam, MT., Tuday, E., Allen, S., et al.[2023]

Dasatinib is an effective targeted therapy for chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemia, showing strong hematologic, cytogenetic, and molecular responses in patients resistant or intolerant to imatinib.

Despite its efficacy, dasatinib can cause significant side effects like myelosuppression and pleural effusions, particularly in advanced-phase patients; however, recent dose optimization has reduced these adverse events without affecting the drug's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Guidelines for the management of dasatinib (Sprycel)-induced side effects in chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemias]. Cony-Makhoul, P., Bergeron, A., Corm, S., et al.[2015]

In a study using SAMP10 mice, which model brain aging, the combination of dasatinib and quercetin significantly improved frailty, motor, and cognitive functions compared to a control group, indicating potential benefits of senolytic therapy in aging.

SAMP10 mice exhibited greater frailty characteristics than normal aging controls (SAMR1), and the combination therapy not only reduced these frailty markers but also positively affected the senescent phenotype in the hippocampus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dasatinib plus quercetin attenuates some frailty characteristics in SAMP10 mice. Ota, H., Kodama, A.[2022]

A clinical study involving 56 volunteers demonstrated that the generic dasatinib tablet (YiNiShu®) is bioequivalent to the branded version (Sprycel®) under both fasting and fed conditions, indicating similar pharmacokinetic profiles.

Both dasatinib formulations showed a good safety profile, confirming that patients can expect comparable efficacy and safety when using either version of the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects. Wang, Y., Xue, J., Su, Z., et al.[2023]

A highly sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to accurately quantify dasatinib and its active metabolites in human plasma, validated over a concentration range of 1.00-1000 ng/mL.

The assay demonstrated excellent precision and accuracy, with high recovery rates and minimal matrix effects, making it suitable for pharmacokinetic studies of dasatinib in patients with chronic myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A validated LC-MS/MS assay for the simultaneous determination of the anti-leukemic agent dasatinib and two pharmacologically active metabolites in human plasma: application to a clinical pharmacokinetic study. Furlong, MT., Agrawal, S., Hawthorne, D., et al.[2015]

In a study of 48 older patients with type 2 diabetes, dasatinib, a senolytic agent, led to a significant reduction in serum glucose levels by 43.7 mg/dL compared to imatinib, suggesting its potential as an effective antidiabetic treatment.

Patients treated with dasatinib also experienced a notable reduction in hemoglobin A1c levels and required fewer daily insulin units, indicating that dasatinib may offer comparable benefits to standard diabetes medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antidiabetic Effects of the Senolytic Agent Dasatinib. Salaami, O., Kuo, CL., Drake, MT., et al.[2022]

The phase I clinical trial involving 5 early-stage Alzheimer's patients demonstrated that the senolytic therapy dasatinib and quercetin was well-tolerated, with no early discontinuations and confirmed CNS penetrance of dasatinib in cerebrospinal fluid.

While the treatment did not show significant cognitive improvements, it provided safety data and insights into potential senolytic effects, indicating a need for further studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial. Gonzales, MM., Garbarino, VR., Kautz, TF., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37261678/

Long-term dasatinib plus quercetin effects on aging outcomes ... Cellular senescence increases with aging and results in secretion of pro-inflammatory factors that induce local and systemic tissue dysfunction.

2. nature.com nature.com/articles/s41598-022-06448-5

Dasatinib plus quercetin attenuates some frailty ... Combination therapy improved frailty, motor and cognitive function, and the senescent phenotype of the hippocampus compared with vehicle in SAMP10.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9924942/

Senolytic drugs, dasatinib and quercetin, attenuate ... Results from this study suggest that D&Q attenuates adipose tissue inflammation and improves systemic metabolic function in old age.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04733534

Study Details | NCT04733534 | An Open-Label Intervention ... The primary aim of this proposal is to test the efficacy of two, short duration senolytic regimens: 1) combination of Dasatinib plus Quercetin and 2) Fisetin ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0360301621010166

108 Senolytic Cocktail Dasatinib Plus Quercetin Enhances ... Here, we present data on the effect of DQ and RT on tumor cells and senescence in a radio-resistant melanoma model in vitro and in vivo. Materials/Methods.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40443429/

Protocol for a pilot clinical trial of the senolytic drug ... This pilot study aims to assess the feasibility and safety of D+Q in older adults with schizophrenia, schizoaffective disorder, and treatment-resistant ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8417260/

Long-term treatment with senolytic drugs Dasatinib and ... Long term treatment with senolytic compounds Dasatinib and Quercetin reduces disc senescence burden and ameliorates age-dependent degeneration in mice.

8. sciencedirect.com sciencedirect.com/science/article/pii/S2213231725002290

Long-term senolytic therapy with Dasatinib and Quercetin ... In summary, our data showed that long-term senolytic therapy with D + Q significantly alleviated retinal degeneration in a mouse dry AMD model through the ...